The IL-6, IL-8, IL-10, and VEGF quartet: A novel circulating cytokine signature for prognostic stratification in hepatocellular carcinoma

Abstract

Background: The systemic inflammatory and angiogenic milieu is a critical determinant of hepatocellular carcinoma (HCC) progression. This study aimed to develop and validate a comprehensive prognostic model based on a quartet of key circulating cytokines: Interleukin6- (IL6-), IL8-, IL10-, and Vascular Endothelial Growth Factor (VEGF). Methods: We recruited 157 treatment-naïve patients with HCC and 50 healthy subjects between January 2019 and December 2022. The levels of IL-6, IL-8, IL-10, and VEGF in serum were measured using a multiplex immunoassay. We developed a Cytokine Risk Score (CRS) based on log-transformed cytokine concentrations using multivariable Cox proportional hazards regression. OS was the primary outcome measure, and PFS was the secondary outcome measure. The prognostic significance of the High CRS vs Low CRS groups was determined using multivariable Cox regression, adjusting for BCLC stage, Child-Pugh score, AFP >400 ng/mL, and tumour size. Results: Serum levels of IL-6, IL-8, IL-10, and VEGF were significantly elevated in HCC patients versus controls (all p<0.001). The derived CRS was an independent predictor of poor OS (HR: 3.42, 95% CI: 2.24–5.21, p<0.001) and PFS (HR: 2.68, 95% CI: 1.82–3.94, p<0.001). The CRS demonstrated superior prognostic accuracy (C-index=0.78 for OS) compared to individual cytokines or alpha-fetoprotein (AFP) alone. Crucially, the CRS effectively stratified patients within Barcelona Clinic Liver Cancer (BCLC) stages A and B into distinct risk subgroups with significantly different clinical outcomes. During follow-up, 86 deaths occurred among the 157 HCC patients, yielding an events-per-variable ratio of 21.5 for the four cytokine predictors included in the CRS derivation model. Conclusion: The composite serum signature of IL-6, IL-8, IL-10, and VEGF, termed the prognostic quadrad, constitutes a robust, non-invasive biomarker for refined risk stratification in HCC. This model captures the interplay of tumour-promoting inflammation, angiogenesis, and immune suppression, offering significant prognostic value beyond current staging systems.